The molecular events that cause ccRCC metastasis remain poorly understood and this is a major contributing factor to why ccRCC mortality rates have been slowly rising for more than three decades. Indeed, current drugs approved for metastatic ccRCC are designed to target molecular alterations that have been reported to be common in primary ccRCC tumors, but not necessarily in metastatic ccRCC tumors specifically. As such, it is not surprising that despite a steady increase over the past decade in therapeutics for metastatic ccRCC, the five year survival is still less than 10%. Thus, a key clinical issue is the need to interrogate ccRCC metastatic tumors in order to identify molecular alterations that are unique to metastatic tumors. It is these alterations that will have the highest probability to enhance prognostic forecasting, predict response to current therapies, and inform the development of novel, targeted therapeutics. In direct response to this need, our multidisciplinary team of investigators has used Affymetrix gene arrays to analyze 14 patient-matched primary and metastatic ccRCC tumors (all metastases are to lung) and identified seven novel candidate genes that are differentially expressed in metastatic versus primary ccRCC: DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. Herein, we propose to expand on our pilot work by (1) validating these candidates in a large independent cohort of well annotated patient-matched primary and metastatic ccRCC tumors that include other metastatic sites in addition to lung, (2) evaluating the association of expression of these genes in the metastatic tumors with survival and treatment response, and (3) expanding our existing efforts to include the exploration of additional metastatic genetic alterations that are associated with prognosis after metastasis. In summary, our overall goal is to better understand the pathogenesis of RCC metastasis in order to help focus tertiary prevention and treatment efforts. By identifying genetic variants that are associated with ccRCC progression from primary tumor to lethal metastatic disease, this project will ultimately have the potential to inform the biologyof ccRCC progression, improve prognostic and response to treatment efforts as well as provide rationale targets for novel therapeutics.